Project Summary Over the last decade, important progress was made to better understand the prevalence, natural history, and potential therapies for nonalcoholic fatty liver disease (NAFLD) and nonalcoholic steatohepatitis (NASH) in the general population. However, similar attention has not been paid to NAFLD and NASH in HIV infected individuals. For example, the prevalence of NAFLD and NASH in the current era of newer antiretroviral therapies (ART), which are less associated with metabolic disturbances, is not well studied. Similarly, There has been important progress in terms of non-invasive tools (clinical decision aids, serum based biomarkers, and imaging techniques) for disease stratification for NAFLD in the general population but similar research focusing at NAFLD in HIV infected individuals is sorely missing. Over the last decade, there have been several large randomized clinical trials to treat NASH in the general population but the majority of them systematically excluded HIV infected individuals. Therefore, we are proposing the following specific aims to better define the burden of and risk factors for NAFLD and NASH in a representative multiethnic cohort of HIV infected individuals and test vitamin E as a potential therapy for those with NASH. First, we will determine the prevalence of NAFLD in 600 HIV infected patients attending multiethnic urban HIV clinics. The influence of alcohol, ART, genetic, metabolic, and viral factors on the risk of fatty liver in these patients will be studied. Second, we will define the prevalence of and risk factors for biopsy-proven NASH and liver fibrosis among HIV infected patients with NAFLD. We will also test and optimize the performance of widely studied non-invasive serum- and elastography-based markers of liver injury and fibrosis against the gold standard, liver biopsy. Finally, we will evaluate the efficacy of vitamin E for treatment of NASH in HIV infected patients. We will perform a pilot randomized placebo controlled trial of vitamin E 800 IU/daily for 6 months in 56 subjects with biopsy-proven NASH. We will evaluate the effects of vitamin E on liver fat content (measured by magnetic resonance imaging) and levels of non-invasive markers of hepatic and systemic inflammation, and systemic oxidative stress. We will also identify baseline liver gene expression signatures that predict response to therapy. These comprehensive and complementary investigations are timely and logical extension of our knowledge acquired from the general population with NAFLD to HIV infected individuals. Upon completion, we expect our studies to delineate the prevalence of and risk factors for NAFLD and NASH and their non-invasive risk stratification in HIV infected individuals. Our proposed clinical trial is expected to establish vitamin E as an excellent and inexpensive candidate for further development as a treatment for NASH in HIV infected individuals. Combined, our proposed specific aims will significantly advance the field of fatty liver disease in HIV infected individuals.